Diabetes is a disease of epidemic proportion. Glucose homeostasis and peripheral tissue glucose disposal are disrupted in diabetics. GLUT4 plays a central role in normal maintenance of insulin stimulated glucose uptake in muscle and adipose tissue. By disrupting the GLUT4 gene we generated a novel model to study glucose homeostasis. GLUT4 null mice have normal glucose tolerance but have peripheral insulin resistance without diabetes. In vitro and in vivo assays have identified an insulin sensitive glucose transport activity (GLUTx) in highly oxidative muscle and brown fat that may compensate for ablation of GLUT4 and is enhanced under hyperglycemic clamp conditions suggesting it is a low affinity transporter/sensor. A putative cDNA encoding GLUTx has been isolated which has sequences in common with facilitative glucose transporters and glucose sensors/receptors. We hypothesize that expression/activation of GLUTx and enhanced muscular oxidative capacity help enable GLUT4 null mice to resist becoming diabetic. GLUTx may be upstream of AMP-activated protein kinase (AMPK) which senses metabolic stress. Thiazolidinediones (TZDs) improve glucose homeostasis by an insulin sensitizing action. Muscles from TZD-treated subjects, like those of GLUT4 null mice, display increased glucose oxidation and reduced glycogen storage. This may suggest altered glucose partitioning in TZD muscle may be due to improved flux through a GLUTx-mediated (non-GLUT4) pathway and/or alterations in the glycogen scaffold protein PTG1. We also hypothesize that TZDs activate signaling mechanisms similar to those with GLUT4 ablation which increase glucose uptake and oxidation possibly through GLUTx and AMPK. As with GLUT4 null muscle, further increases in glucose oxidation may be seen in TZD-treated muscle under hyperglycemic clamp conditions. These hypotheses will be tested in GLUT4 null and wild type mice following TZD treatment. By understanding alterations in signaling, glucose partitioning, and expression of GLUTx and PTG1 in wild type and GLUT4 null muscle of these mice under euglycemic and hyperglycemic conditions we may identify novel targets for therapeutics for type II diabetes and other diseases of insulin resistance.